TW299236B - - Google Patents

Description

299236 A6 B6 V. Description of the invention (/) The present invention and the controlled release of one or more active ingredients of the B-drug compound are not good. In particular * the present invention relates to the controlled release of B-progenitor compounds of 112-antagonists, hemagglutinin agonists or antagonists. British Patent No. 1397436 discloses CimeUdine, N-cyanomethyl-N ”-[2-[[(5-methyl-1H-quinazol-4-yl) methyl] ] Ethyl] guanidine, and its acceptable salts B. Ganzhou patent specification No. 431877 discloses that Simpyridine and its B-acceptable acid-addition salts can be delayed-release oral agents. Simpyridine is a kind of ammonium H2-antagonist. Ranitidine * U- [2-[[[[5- (dimethylamine) methyl-2-furanyl] methyl] thio] ethyl] methyl-2- Nitro-1, ethylene diamine and its acceptable salts are described in British Patent Specification No. 156 5 966, and its special crystalline form of ranipyridine is described in GB-B-2084580. The two specifications disclose a variety of formulations, including oral, topical, parenteral or rectal formulations. The oral formulations of ranididine (GB-B_2142820, GB-B-2198352, GB-B-2218336 are further disclosed , GB-B-2219940, GB-B-2222772 and GB-A-2229094) ° Dinipyridine is a potent H2-antagonist, its hydrochloride form is widely used in the treatment of lowered acid Illness. These Symptoms include duodenal and ulcers, reflux esophagitis, and Zollinger-Ellison syndrome. Ranipridine can also be used as a preventive agent in surgical operations. Allergies and inflammations. Medium 4 (21〇X 297W issued) (Please read the precautions on the back before filling in this page) .Wo • Ting · .Green · A6 _B6 Fifth, the invention description (1) (please first Read the precautions on the back and fill in this one hundred) British Patent Specification No. 21 62522 reveals the serotonin S2-activator Sumatriptan, 3- [2- (dimethylamino) ethyl]- N-methyl-1IL-indole-5-methanesulfonamide is a high-performance compound for the treatment of migraine. Sumatralide is best used in the form of its succinate axillary. Immediate release and sustained release The preparation of dosage forms is well known. Recently, a dosage form that provides rapid release of the active ingredient after the initial time has been disclosed has been disclosed, which is later called a pulsatile release dosage form .. British Patent Application No. 2230185 A describes a Shuangli oral lozenges, one layer of which contains the immediate release The layer contains a sustained-release lozenge. Therefore, this lozenge is essentially made up of two combined dosage forms. The problem with the lozenge type lozenges is that they cannot be easily and efficiently prepared by conventional tablet-making machines. • Fight · Huanzhou Xiaoli Application No. 3845 No.14, which is a tablet of M-type 4 'lozenges, "medicine compound" • It provides a continuous dose of active ingredient after the immediate dose of active ingredient. • Line. For example, * British Patent Specification No. 22 30 441 Α discloses a pulsating fusiform. The described dosage form contains a two-part capsule that contains a water-swellable material that can separate the capsule parts when inflated. This dosage form is quite expensive and difficult to manufacture. A major problem is to provide pulsatile release formulations that use conventional excipients and can be prepared using traditional tableting machines. Another problem arises when it comes to the manufacture of pulsatile release dosage forms containing highly water-soluble active ingredients such as drinipridine. Some pulsatile release devices only rely on the external calendar containing polymer. When k contacts the intestinal flow surface, hydration forms _ 4 «» A 4 (210X 297X) ^ 99236 A6 B6 V. Description of the invention ('> ) A glue matrix. European Patent Application No. 384514 describes such equipment. In this device * once the outer mushroom partly dissipates * will form a loose gel-like structure, and the intestinal fluid will moisten the inner lozenge. If the lozenge contains a highly water-soluble active ingredient, the ingredient will leak hydrocarbons from the partially dissociated outer layer, causing premature and unpredictable release and a non-discriminatory pulse * • The result is reduced absorption And insufficient plasma concentration. It is also problematic to prepare pulsatile release doses when a considerable dose of active ingredient is required, especially for oral preparations. The core of this dosage must be large *, so if the swallowing is to be maintained easily, the thickness of the outer layer will be limited. If the active ingredient is water-soluble, the problem is even greater, because if the external mushroom is very thin, the drug will leak through the thin outer layer and cause unpredictable and premature release. We have now discovered that conventional excipients and tablet machines can be used to prepare dosages with the following functions, for example: i) pulsatile release of the active ingredient; ii) immediate release of the first active ingredient * followed by the second active ingredient Release; iii) the buried active release of the active ingredient; iv) the sustained release of the first active ingredient and the delayed release of the second active ingredient; v) the immediate release of the first active ingredient * followed by the second active ingredient Continuous release can be selectively followed by pulsatile release of more active ingredients. The pharmaceutical compound of the present invention has the advantages of pulsatile release, ore holding release and / or delayed release dosage forms. Therefore, the allowable activity of the B-drug sister compound of the present invention (please read the precautions on the back before filling in this page) • Pack.. Order. • Green. A 4 (210X 297 public) A6 ____B6 V. Description of the invention () Ingredients Reduced number of doses • Enhances the patient ’s ability to receive and can be released when the patient is inconvenient to administer medication, for example, when the patient is sleeping expensively, it can also be administered before the symptoms begin. Furthermore, the oral and eye dosage forms can control the location of drug delivery, and the optimal plasma concentration of the active ingredient is maintained by K. The dosage form of the present invention can combine the advantages of pulsatile release, sustained release and / or delayed release dosage forms. In particular, the dosage form of the present invention can implement a very complicated dosing plan without painful use of many different dosage forms. This is particularly useful when you want to take the active beer on your own, because you do n’t have to rely on the patient to remember that there are many different dosage forms for the eye during various periods of time. The S compound of the present invention can also provide a different pulsation without premature leakage of the active ingredient from the core, even when using a highly water-soluble active ingredient such as ranidine. The "pharmaceutical compound" of the present invention can also be quickly adjusted to provide the desired special "time versus pulsation" value. Lozenges with the same size will have K-predictable release properties with few variations between batches. Even when the thickness of the outer coating is limited, that is to say, when the box requires a large amount of active ingredients and the active ingredients are highly water-soluble, the B-drug compound of the present invention can provide reliable pulsatile release. Therefore, the present invention provides a medicinal composition comprising: an outer layer comprising a pH-independent hydrophilic polymer K and one or more fillers; and (b) one or more inner layers, each layer comprising an active ingredient; Among them, the outer layer is gradually removed by dissolution and erosion after the drug is applied, and the internal calendar A 4 (210X297 g; * ί) {please read "Notes on the back of the competition and then fill out this page] 2. Description of the invention () It is gradually removed by dissociation and immersion alone or disintegrates rapidly during the storm. In a preferred or selective case, the inner layer disintegrates rapidly upon exposure. A better way is that the osmanthus compound of the present invention has one or two inner core layers containing active ingredients, or more preferably a single inner core layer. In a preferred or optional case, the B-sibling compound of the present invention additionally supplies a rapidly disintegrating outer coating, surrounded by an independent hydrophilic polymer layer, which contains an active ingredient. In a preferred or buried condition, when the additive containing an active ingredient rapidly disintegrates the outer coating is present, or when the internal calendar is exposed to ®, it is gradually removed by dissolution and erosion. The outer layer contains an independent hydrophilic polymer M and one or more fillers * with an active ingredient. In a preferred or optional case, the outer layer contains an independent hydrophilic polymer and one or more fillers • and is almost completely free of any active ingredients. In a preferred or optional case, the paniculone compound of the present invention additionally provides an enteric coating, surrounded by an independent hydrophilic polymer. The pharmaceutical composition of the present invention may be in any general dosage form * especially for oral, rectal or vaginal swelling, such as lozenges, suppositories and vaginal suppositories. Suitable active ingredients for use in the β-sister compound of the present invention include analgesics, anti-inflammatory agents, bronchodilators * such as Shuchuanning (Ralbutamo 1), sleeping pills, antihypertensive drugs, steroids, anti-migraine compounds, such as Serotonin agonists, such as tamatridan and H2-antagonists. Other types of active ingredients include medicines for the treatment of Xia'er pipeline diseases, A4 (21〇X 297 异 发) (please pay attention to the notes on the back before filling this page) A6 ___B6 5. Description of the invention () For example, allergic bowel syndrome * As described in EP-A-0501322 heme hormone agonist * especially 5-fluoro-2-methoxy-1H-indole-3-carboxyl Acid [1- [2-[(methylsulfonyl) amino] ethyl] -4-hexahydropyridyl] methyl ester and its medically acceptable salts and solvates. Other suitable active ingredients include the 5HT3 serotonin antagonist Ondansetron (Ondansetron) and its unacceptable salts and solvates • such as hydrochloride dihydrate; 2, 3, 4, 5-4 Hydrogen-5-methyl-2-[(5-methyl-11_-imidazol-4-yl) methyl] -111_-pyridine [4,31)] indol-1-one and its And solvates, such as hydrogen atmosphere salts; (+)-1,2,3,9-tetrahydro-9-methyl-3 [(5-methyl-1H-imidazol-4-yl) methyl]- 4H-carbazol-4-one and its B pin can accept salts and solvates, such as hydrochloride · 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 [(5 -Methyl-UL-imidazol-4-yl) -methyl] -llL-pyridine [4,3-b] indole-l-_ and its B pharmacologically acceptable a! Class and solvates. The pharmaceutical composition of the present invention may contain a 5HT3 antagonist, such as ondansetron, and one or more other antiemetic compounds, such as dexamethasone (dexaaethasome) ° Preferably, the pharmaceutical composition of the present invention B contains asthma Ning • It is better to include a serotonin agonist, such as tamotriptan * hemagglutinin antagonist * such as 5-fluoro-2-methoxy-1H-indole-3-carboxylic acid [1- [ 2-[(Methylsulfonyl) amino] ethyl] -4-hexahydropyridyl] methyl ester and its »acceptable salts and solvates. Therefore, in a preferred or selective aspect * The present invention provides a B Hui sister compound * which contains: A 4 (210X 297 public hair) (please note the back of the moraine before writing this page) • Pack ·-Order · • Edge · A6 __B6 5. Description of the invention () An outer layer containing an independent hydrophilic polymer M and one or more fillers; b) An inner layer core containing an H2-antibody; where the outer After dissolving the drug, it gradually dissolves and soaks and removes the animal. The inner core quickly disintegrates during the tyrant. In a preferred or selective aspect * The H2-antagonist-containing »pharmaceutical compound of the present invention additionally contains a rapidly disintegrating outer coating * which surrounds an independent hydrophilic polymer layer. H2-antagonist to provide immediate release weighing. In a preferred barking situation, the h2-antagonist is ranipridine, simidine, sufotidine, famotidine, roxatidine, or nicotine. Shasha is steep, preferably Sim is steep, and ranipyridine is even better. The term "ranipyridine" includes its acceptable salts. The salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate K, and organic acids. Emulsions, such as acetate, maleate, sodium peroxylate, fuyuate, and ascorbate. A particularly preferred salt is neotanoate. The B-sister compound containing the Hz-antagonist of the present invention may be in any suitable form, especially a dosage form suitable for the eyes and eyes * such as lozenges. In a preferred or selective case, the present invention also provides a road drug compound comprising: < a) an outer layer containing an independent hydrophilic polymer K and one or more fillers; A4 (21〇X 297 public) (Please read the precautions on the back before filling in this page) ^ · • Tack · A6 B6 V. Description of invention () < b) An inner core containing Sumatra Dan; The external calendar gradually dissolves and erodes after hydrocarbon casting and removal • The inner core quickly disintegrates during the beta. In a preferred or rational case, the B-medicine compound of the present invention containing Sumatriptan also contains a rapidly disintegrating outer coating * surrounded by an independent hydrophilic polymer layer containing Matritan * K provides immediate release medication. The present invention contains Sumatralide's "pharmaceutical compound can be used in any suitable dosage form • especially for oral, rectal, or rectal dosage forms * such as lozenges and suppositories. When the ® compound in the sister compound of the present invention is removed “gradually” * this means that this level is removed within a period of time, for example within 1 to 8 hours. Such as 1 to 3, 5 hours, 2 to 5 hours, or 4 to 6 hours after casting. When the layer in the sister compound of the present invention disintegrates "rapidly", it means that the layer disintegrates within a period of time, for example within half an hour M, such as within 10 minutes after exposure. It should be recognized that the rapidly disintegrating inner layer of the sister compound of the present invention will only begin to disintegrate when the independent hydrophilic polymer has been removed on the outside and part or all of the internal calendar has been destroyed. The term "wcH independent hydrophilic polymer" is popular among those who are familiar with this art. This polymer dissolves / erodes at an unfavorable rate of M and the value of the surrounding fluid after casting. This type of polymer includes kinetin Ether, polyvinylpyrrolidine_, a mixture of natural hydrophilic gums such as guar gum, carrageenan (Uaraya), yarrow knee -10-A 4 (210X 297 public hair) (Please read the precautions on the back first (Fill in this tile again) • Chi. • Hit · • Green ·

A B 5. Description of the invention (), and synthetic biopolymer glue • and its mixture. It is preferred to use fipronyl ether. The most preferred is hydroxypropyl methylcellulose. The filler used in the tablet of the present invention is a filler well known to those skilled in the art. Such fillers may be engraved or non-dissolvable, and may be swellable or non-swellable, including, for example, microcrystalline cellulose, divalent calcium phosphate, trivalent calcium phosphate, calcium carbonate, calcium sulfate, right Sugar, kaolin, lactose, powdered cellulose, prospected starch, starch, sucrose K and mixtures thereof. The preferred fillers include microcrystalline carbyrazine M and divalent calcium phosphate. Other excipients that may be used in the polymer layer include slip agents used in this technique, such as magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium fumarate stearate, hydrogenated vegetables Oil, glycerin palm stearate, glyceryl gluconate, sodium benzoate, sodium laurate, magnesium laurel sulfate, milled oil, talc, and mixtures thereof; the slip agent used in this technique * is colloidal two Silicon oxide; the disintegrant used in this technique, such as calcium carboxymethylcellulose, carboxymethylcellulose sodium, magnesium aluminum silicate, microcrystalline vitamin, Placacilin potassium, pre-gelatinized Starch, sodium alginate, sodium starch glyphosate, and mixtures thereof; surfactants used in this technique, such as anionic (such as sodium laurate), maleic or neutral surfactants; This technology »conventional seed salt (such as chlorinated sodium); dyes and pigments that are commonly used in pharmaceutical technology. A preferred lubricant contained in the polymer is a stearic acid sodium fumarate. Contained in the polymer A preferred slip agent in the layer is colloidal silicon dioxide. In a preferred In the state of distress • The outer polymer layer contains a kind of independent pro-11-A 4 (21〇Χ 297 issued) (please read the precautions on the back before filling the nest page) • Install · • hit ·, line · ^ 0236 Five 'invention description ()

Aqueous polymer (such as hydroxypropyl methylcellulose), one or more fillers (such as microcrystalline androgens, divalent calcium phosphate), a lubricant (such as sodium fumarate stearate), and a slip _ (E.g. Colloidal dioxide sand) ° It is preferred that the outer «contains 20 to 85 weight percent of an independent hydrophilic polymer, preferably hydroxypropyl methylcellulose. For example, 20 to 40 weight percent. Quickly In addition to the active ingredient M, the disintegrating inner layer M and the rapidly disintegrating outer layer may contain excipients such as fillers, binders, disintegrating agents and lubricants. The embedded filler, disintegrant and lubricant are as described above. Combined binders include methicone, carboxymethyl thyroxine, hydroxypropyl methylcellulose, thin acid, ethoxylated vitamin, acacia, gelatin, pregelatinized starch, sucrose syrup , Polyvinylpyrrolidone K and guar gum. In a preferred case, the rapidly disintegrating inner layer and the rapidly disintegrating outer layer contain, in addition to the active ingredient M, one or more fillers (eg microcrystalline cellulose, nougat), binders (eg polyvinylpyrrolidone, pre Gelatinized starch), disintegrants (e.g. microcrystalline entangled vitamins, pregelatinized starch) and lubricants (e.g. sodium fumarate stearate, magnesium stearate). The rapidly disintegrating inner layer and the rapidly disintegrating outer coating can easily achieve the same success. In the present invention, when the drug compound (ie, lozenge) is in the form of enteric coating, it will delay the start of the erosion / disintegration of the independent hydrophilic polymer layer lined until the lozenge reaches the gastrointestinal duct Until the area where the special value is popularized. -12-{Please first read the notes on the back and then fill in this page) • Installed • • Played • Green • A 4 (210Χ 297 public) A6 _B6 5. Description of the invention () (please read the notes on the back Please fill in this page for more details.) This enteric-coated tablet allows the colon to settle the colon * whether it is a direct local action, or it can pass the medicine to a better location. The enteric coating used in the lozenges of the present invention is a coating known to those skilled in the art. Such coatings include cellulose acetate peptidoate, polyethylene acetate oxalate a, shellac, styrene maleic acid copolymer, methacrylic acid copolymer, and hydroxypropyl methyl quasivinoxate. When the b-drug compound of the present invention is coated with an enteric coating, it can be particularly used to treat lower bowel duct diseases, such as irritable bowel inflammation. Therefore, when the B-drug sister compound of the present invention contains the compound described in EP-A-0501322 as an active ingredient * for example 5-fluoro-2-methoxy-1H-indole-3-carboxylic acid [1- [2 -[(Methylsulfonyl · amino) amino] ethyl] -4-piperidinyl] methyl ester and its pharmacologically acceptable B and solvates * It is preferred that it contains an enteric coating. • Beating • When the B-drug compound of the present invention contains H2-antagonists or tamatridan • They will not contain enteric coatings. .Green · When the inner layer gradually dissolves / soaks the surname * In addition to the active ingredients, it may contain a standing hydrophilic polymer K and one or more fillers as defined above, in addition * It also contains as defined before Μ Excipients * such as wine slips, disintegrants, surfactants, ionic salts. The concentration of the active ingredient in the inner or outer layer or the outer coating depends on the active ingredient used * and is 30 to 100% by weight relative to other excipients in this layer. So, for example, in the case of Sumatritan, the combined maid degree is 50% by weight (succinate) * For ranidine, the suitable maid degree is 95% mile (hydrogen atmosphere) Acid salt). -13-A4 (210Χ 2971 :; »**) A6 _____B6 V. Description of invention () (please read the precautions on the back before filling this page) The weight ratio of the inner layer to the outer layer polymer is 1: 1 to 1 : 5 in the Fan Garden, such as 1: 1.3 to 1: 4.3. The weight ratio of the inner layer to the outer rapidly disintegrating coating is 1: 1. The greater advantage of the present invention is that the B-drug compound (such as the pulsatile release compound) is made to have a predictable and uniform release rate (that is, the time-to-pulse ratio is predictable and will not be determined by individual Depending on the dosage form). According to the invention, for a fixed outer and inner layer, the release properties of the formulation depend on the thickness of the outer hydrophilic polymer coating. Therefore, if the pharmaceutical compound is formulated to have a uniform release property, it is important that i) the coating thickness of each preparation should be uniform * and that each preparation should be effectively kept constant; and ii) each preparation The weight of the polymer coating should be kept constant between each formulation. Conventional ingot making methods can be used to conveniently coat polymers of the present invention with known precise weights of polymers.

Therefore, in a further or optional case * The present invention provides a variety of B lotus preparations * The maximum change in the weight of the outer polymer layer does not exceed ± 5% (eg ± 2%) of the average weight of the outer polymer®. ♦ In a further or optional case • The present invention also provides a variety of pharmaceutical preparations whose maximum change in the thickness of the outer polymer layer does not exceed ± 5% of the average thickness of the outer polymer layer (for example, ± 2%). A variety of S lotus preparations mean that the production of such preparations is either • the method prescribed by the practicing division B, or bottled, boxed • small package or bundled -14- A 4 (210X297 i: hair)

6 6 A B Fifth, the formulation of formula (). Using the Futong tablet method, the drug B compound of the present invention can be easily prepared, and the outer polymer layer of each individual drug B preparation can be evenly distributed on the surface of the preparation. Therefore, the present invention further provides a pantaceous sister compound whose thickness difference between the thinnest part of the outer layer and the thickest part of the outer layer does not exceed 5% (for example, 2%) of the average outer layer thickness. It is important to realize that * so that a predictable and uniform release can be obtained * Even if the polymer layer outside the B-pin formulation is not evenly distributed on the surface of the formulation, for example, the core of the device may be offset from the center * At this time • The ratio of time to pulsation will depend on the thickness of the outer polymer layer at the thinnest point. Therefore, the present invention further provides a compound composition of Doppelin B, the thickness of the thinnest part of the external calendar has a maximum change that does not exceed the average thickness of the thinnest part of the outer layer by 5% (for example, 2% of the soil). In further or alternative cases, the present invention provides a variety of pulsatile release dosage forms whose maximum change in time to pulsation does not exceed ± 5% (e.g. ± 2%) of the average time to pulsation. Under better circumstances • The relief release of the present invention provides a different kind of pulsation, that is, after an initial predetermined time delay, it occurs within a relatively short period of time (ie, less than 30 Minutes • for example within 10 minutes) the active ingredient from the core is released and there is no active ingredient and the core leaks prematurely. The medical compound of the present invention can be based on the active ingredient, the administration route, and the patient's * 15 " A4 (210X 297W; ¥) (please read the precautions on the back before filling in the Luan page). • Fate · A6 B6 V. Description of invention () {Please read the precautions on the back before filling in this page) Age and condition are adjusted to provide various unit doses • Suitable agents will be immediately available for those who are hot Known by technical people. Therefore, in the case of Sumatriptan, a suitable unit dosage is 0.1 ng to 100 ng, for example, 2 ng to 40 ¾ g of active ingredient per unit dose, such as 50 mg of Sumatran succinate. This unit dose may be administered 1 to 4 times per day • preferably 2 times. When the B-compound of the present invention contains ranidine, the convenient unit dose of ranidine is 50 to 800 ng, preferably 75 to 600 ng, for example 150 ng of free base. This unit dose may be administered 1 to 4 times per day, preferably 2 times a day. When the medical compound of the present invention contains Simpyridine * The convenient unit dose of Simpyridine is 200 mg or 40 mg of free sickle. • When the B compound according to the present invention contains a compound described in EP-A-0501322, the convenient unit dosage of the active ingredient is 1 mg to 100 mg of free base, which can be administered 1 to 4 times a day . • Green · The present medicinal composition can be designed to deliver a variety of unit amounts * For example, the pulsatile release of the present invention can provide an immediate agent S of the active ingredient, which is then provided after a predetermined time delay Subsequent dosage • Therefore, the number of administrations can be reduced. The time-to-pulse ratio depends on the active ingredient used and the condition to be treated. Therefore, in the case of Sumatrilide, the B Hui sister compound of the present invention conveniently provides an immediate dose of Sumatrilide •• After being buried for a period of 1 to 6 hours (for example, 1 to 3.5 hours) There are more doses. Or, -16-A 4 (210X 297 Yunfa)

6 6 A B V. Description of the invention () The dosage of pulsatile Sumatralide Dan can be taken at the same time as the traditional Sumatralide tablets to obtain the same immediate / buried release properties. The pulsatile release compound of Sumatrilide of the present invention can be particularly used for the treatment of patients suffering from a predictable cluster headache at night. * The pulsatile release dosage form of this patient can be administered. • For example, 6 hours after casting. When the sibling compound of the present invention contains ranidine, it can be designed to deliver (eg, immediately) a unit dose of ranidine (eg, 150 ng) * followed by a predetermined time delay (eg 2 to 5 hours) • There is a unit dose of ranidine (eg another 150 mg dose). When the road drug compound of the present invention contains Simpyridine, it can provide an immediate dose of Simpyridine (for example, 200 or 400 ng) * followed by a pre-set time to provide more doses Simpyridine (eg 200 or 400 ng). The B-drug compound containing the H2-antagonist of the present invention is particularly effective in the treatment of reflux esophagitis or diseases that cause high secretion of mayonic acid (e.g., Left Ringer-Ellison syndrome). When the pharmaceutical compound of the present invention contains a medicinal agent for the treatment of lower intestinal duct diseases * for example described in ΕΡ-Α-0501322. Compounds, especially 5-fluoro-2-methoxy-1H-indole-3- [1- [2-[(Methylsulfonyl) amino] ethyl] -4-hexahydropyridyl] methyl esters of tamoic acid and their ginseng acceptable salts and solvates can be designed to After a predetermined time delay, the unit dose can be delivered properly. If it is coated with an enteric coating, the time delay is (for example, 6 -17-A 4 (210X 297 public)) (please read the continued back first (Notes and fill in this page) • Install. • Hit the line • A6 ____B6 5. Description of the invention () (please read the notes on the back before filling out this page) to δ hours), or if it is not enteric For clothing, the time is 4 to 6 hours. To adjust the rate and method of active ingredient release, the following factors are important factors in designing the dosage form of the present invention: 1. The rate of polymer hydration. A self-contained polymer will be easily buried. • It will quickly make a gel to form a glue layer. The fastest form of the M protectant will dissolve or disintegrate in the most internal form. If the polymer is too slow to hydrate, the fluid may penetrate into the core and cause the early release of the lute. Another consequence of insufficient polymer hydration rate may be the accelerated dissolution of water-soluble excipients in the polymer layer, causing premature disintegration of the dosage form. The polymer hydration rate can be manipulated by changing the ratio of methoxy M and hydroxypropyl groups of the polymer. • Hitting • For example * in the hydroxypropyl methyl cellulose group • There is a significant difference in polymer hydration rate. This is due to the different proportions of the two chemical components attached to the cellulose main bond of HP MC, hydroxypropyl and methoxy substituents. The methoxy substituent is a fairly water-resistant component and does not become a powerful factor in the hydrophilic nature of the polymer and the rate of hydration that constitutes it. However, the propyl group is a powerful factor for the hydration rate of the polymer. Therefore, by changing the ratio of methoxy and hydroxypropyl groups of the polymer, the hydration rate of the polymer can be changed. 2. Particle size. The particle size of the polymer can significantly affect the rate of polymer hydration. The generally preferred way is to use a small particle size out of independent -18-A 4 (210X 297W issued) A6 ____B6 V. Description of the invention () polymer (such as hydroxypropyl methyl phase vitamin) to ensure rapid polymer The characteristics of hydration, painting, and painting will allow some control over the compression characteristics of the dosage form. The particle size of the filler or any additional excipients in the polymer layer may have a significant effect on the release characteristics. Generally, the fine particle size of the insoluble filler will be better, and it will help the polymer layer to be more uniformly etched. 3. Viscosity of polymer solution. The rate of penetration of the surface glue layer into the dose is dominated by the viscosity of the glue M and the degree of immersion. The release of the active ingredient can be controlled by selecting independent hydrophilic polymers with different bond lengths and different viscosities . Higher viscosity polymers cause delayed release of more active ingredients. 2% concentration in water • A polymer with a normal viscosity of about 100 cps is preferred (CPS: centipoise). 4. Polymer concentration. Increasing the concentration of the hydrophilic polymer relative to the other components of the outer layer increases the viscosity of the adhesive formed on the dose surface. Therefore, increasing the level of polymer used will usually result in a greater delayed release of the active ingredient. Increasing the polymer concentration also tends to reduce the sensitivity of the formulation to changes in particle size or hydration rate of the polymer. 5. The existence of lyophilic / non-dissociative and swellable / non-swellable fillers. The dissolvable filler in the polymer layer may affect the viscosity of the surface of the agent. The lyophilic materials will compete with the polymer for water supply. -19-A4 (210Χ 297 gong) (please read the precautions on the back and then fill in this page) • Pack ·. Order · • Green · A6 B6 5. Description of the invention () The release of the insoluble filler is through a dip The animal journey happened. When the polymer melts to a new level, the insoluble filler will be released. The combination of expansive and non-expandable fillers in the outer polymer layer will be controlled to prevent stress cracking from occurring on the polymer layer and cause the core to disintegrate early. This is the preferred method. Generally, insoluble fillers should be used in fairly low maize degrees * for example, less than 15% by weight of the dose. The lesser way is to use non-soluble but swellable fillers * such as microstructured crystalline cellulose. Therefore, the release characteristics are corrected, because the swell rate changes, but no crushing will occur. 6. The presence of surfactants and ionic salts. When ionic salts are used in the formulation of the polymer layer, they compete with the polymer for water that changes the hydration rate of the polymer. The surfactant contains anionic surfactants, such as sodium laurel sulfate, which can increase the higher viscosity and slower release that may be expected. 7. The thickness of the outer polymer layer. As the thickness of the outer polymer layer increases, the release time of the active ingredient in the inner core also increases. The correction of the surface-to-volume ratio of the dose may also almost completely change the release characteristics. The compound of the present invention can be prepared using a traditional tablet-making machine, a conventional method known in this art. • Therefore * For example, an independent hydrophilic polymer can be mixed with one or more fillers and optionally other excipients and compressed onto one or more cores each containing an active ingredient. -20-A4 (21〇X 297; ¥) (please read "Precautions on the back and then fill in this page"). Install · Play .. Green. A6 B6 5. Description of invention () Can be compressed The active ingredient core is prepared by mixing materials prepared by dry blending, wet granulation, or dry grain mixing. The rapidly disintegrating outer coating mixture can be prepared in the same way and compressed onto a core coated with an independent hydrophilic polymer. The present invention is further illustrated by the following non-limiting examples * The following examples are particularly aimed at oral lozenges, however, depending on the shape of the formulation Dong * Suppositories and vaginal suppositories commonly administered to the rectum and vagina can be used by The same core and coated sister were made. Example 1 Pulsatile release lozenge weight percentage M fluoropyridine 20 microcrystalline prodrug 59 pregelatinized starch 15 polyvinylpyrrolidone 5 sodium fumarate stearate 1 polyacrylonitrile is used as a gelling fluid to make a hammer Fluopyridine is mixed with microcrystalline quasi-vitamin, pregelatinized powder, polyvinylpyrrolidone and granular mixture. Air-dried granules * Screened with Μ, and mixed with sodium fumarate stearate in a suitable tablet press before compression * Κ produced 50 mcg core tablets containing 10 mg of saflupyridine Its diameter is 4.76 mm and its thickness is 3.0 mm. -21-A4 (issued 21〇X 297W) (please note the back of the sulfonate first and then fill in this page). Install • • Play. • Green • A6 B6 5. Description of the invention () Outer layer replacement percentage hydroxypropyl Methyl androstin "35 Microcrystalline cellulose 40 Divalent phosphorus_calcium 23 Colloidal silicon dioxide 1 Nafumarate stearate" 1 Beta 2% normal viscosity in water = = 100 CPS (centipoise) ( Please "Read the precautions on the back and then fill out this page." The excipients should be mixed with K and use a synthetic mixed core tablet compression coating to make 265 gram tablets. The diameter is 8.7 mm and the thickness Play. 4.0 mm. Use a dissolution tester that complies with USP regulations to monitor drug release in lozenges. * Here, 500 l of distilled water or artificial liquid or artificial liquid should be maintained at 371 and used as a dissolution medium. The dissolution method of USP 1 is used at a speed of 250 revolutions per minute. • Green. The pulsatile release of saflupyridine in each broodstock was measured after approximately 3.5 hours. In Examples 2 to 9 shown below • The volume of the lozenge core and polymer coating is similar to Example 1. Example 2 -22-A4 (210X 297W) A6 B6 V. Description of the invention () Pulsatile release lozenge saflupyridine 20 Microcrystalline fibrinogen 59 Pregelatinized starch 15 Polyvinylpyrrolidone 5 Nafuma stearate Salt 1 (please read the precautions on the back before filling in the nest page). Pack · Hydroxypropyl methyl vitrin * 77 Microcrystalline Panwein 12 Divalent calcium phosphate 9 Colloidal silica 1 Stearic acid Nafumarate 1 • Beat • • Green. Normal viscosity of β in water at 2% = 100 centipoise pulsatile release tablets are prepared and tested as in Example 1. The pulsatile release of the active ingredient in the artificial intestinal juice was measured after approximately 9.2 hours * and the pulsatile release of the active ingredient in distilled water or artificial night was measured after approximately 6.2 hours. -23-A4 (210X 297 male; * #) A6 B6 V. Description of the invention () Example 3 Delayed sustained release lozenges Hydroxypropyl methyl vitretin * 35 Microcrystalline secondary vitamin 40 Divalent calcium phosphate 23 Colloidal silica 1 Nafumarate stearate 1 (please read the notes on the back before filling this page) k.-2% normal viscosity in water = 100 centipoise. Compress according to the example The lozenge core of Example 1 was coated and tested according to the method described therein. Sustained release of the active ingredient in the human solution is obtained after a 3-hour extension period. • Line. Example 4 Pulsatile Released Tablets Lozenges Core Weight Percentage -24 * A4 (210X297 Public) A6 B6, Description of Invention () Shuchuanning Sulfate 19.28 Microcrystalline androgen 64.72 Pregelatinized starch 15.00 Nafumarate stearate 1.00 Mixes succinic acid and excipients, and compresses the mixture in Tongdan lozenge pressed eaves to produce a lozenge core containing 8 mg of succinic acid base. Outer layer (please read the precautions on the back before filling in this page) Weight percentage Hydroxypropyl methyl-grade vitamin 30 Microcrystalline crystalline vitamin 43. Divalent calcium phosphate 25 Colloidal silicon dioxide 1 Nafionate stearate Horse salt 1 • Pack. • Beat. • 2% normal viscosity in water = 100 centipoises • Green. The pulsatile release of Shuchuanning in each sickle dissolution medium is measured after about 3 hours. Example 5 The continuous release of the first active ingredient and the delayed release of the second active ingredient delay the release of the first active ingredient in the entire polymer base "in * the polymer base-2 5-A 4 (210Χ 297 male; Ϊ ) A6 B6 V. Description of the invention () The body includes hydroxypropyl methyl androstin (2% normal viscosity in water = 100 centipoise) (30% by weight) · Microcrystalline susceptible vitamin (43% by weight) ), Divalent calcium phosphate (25% by weight) »colloidal silica (1% by weight) and sodium fumarate stearate (1% by weight). This mixture was compression coated to prepare a core tablet containing the second active ingredient as described in Example 1. The sustained release of the first active ingredient and the extended release of the second active ingredient were measured. Example 6 A lozenge with a pulsatile release of the first active ingredient and a sustained release of the second active ingredient disperses the first active ingredient throughout the polymer matrix, which includes hydroxypropyl methyl lycopene (2% in water Normal viscosity = 100 centipoise) (30% by weight), microcrystalline crystalline vitamine (17% by weight) · M and divalent calcium phosphate (13% by weight). Disperse the second active substance throughout the excipient base * The polymer matrix includes hydroxypropyl methyl cellulose (2% normal viscosity in water = 100 centipoise) (77% by weight) · microcrystalline Androstin (12% by weight), divalent calcium phosphate (9% by weight), colloidal silica (1% by weight) Μ and sodium fumarate stearate (1% by weight). Compress the mixture * K to coat the polymer matrix of the first active ingredient. The resulting tablet is further compressed and coated. The pulsatile release of the first active ingredient and the sustained release of the second active ingredient were measured -26-A4 (210X 297 g; ί) (please first «read the precautions on the back and then write this page). Pack. • Hit. • Fate · Mingfa Mingfa 5 7 tablets of release and release control of the actual case

A B and. M is the core of the packaging agent. The core material contains the above-mentioned package, which is the most pre-made, and the base agent is the shape forming body, the base material, the most mixed agent, the film, the formula, the tablet description, the yu6 nuclear example, the preparation and the description. . Therefore, the actual shrinking step of the clothing and the clothing bag is as follows: after pressing it into the release artery, the most sustained release is to continue to release the drug immediately after the release (please first «Just note the back and then write the book Page) • Packing. This core tablet can also be manufactured by choosing an appropriate excipient mixture I, so it can replace the core disintegration, it produces swelling, causing sustained release of the final active substance • instead of pulsatile release . Example 8 The green sapyridine core lozenge (manufacturing method is as described in Example 1) is a shrink coat, which uses a 74.4% by weight HP MC (nominal viscosity, 2% in water = 100%) · 11.6% by weight microcrystalline androgen * 8.2% resuspended dibasic calcium phosphate · 3.3% by weight Piroxicam, 0.97% by weight colloidal silica M and 0.97% by weight stearin Acid fumarate.

The release of the drug from the lozenge is monitored using a dissolution tester that complies with USP regulations, where * 5000 liters of gastric fluid should be kept at 37 degrees and used as a dissolution mediator. Use this USP 27-A 4 (210X 297 2 shots) at a rotation speed of 250 revolutions per minute A6 B6 V. Description of the invention (1) Dissolution method. Sustained release of piroxicam and release of saflupyridine in response to movement were obtained. Example 9 Saflupyridine pulsatile release lozenges were prepared by the method described in Example K. These lozenges are given a casing by sprinkling a solution containing methacrylic acid polymer and triacetin (90: 10) into the lozenge in isopropanol. Sai casings are insoluble at an output value of 6.0M • The same is true in natural or artificial fluids. However, this coating is dissociative in the digestive tract area with an output value higher than 7. The release of the drug from the lozenge is monitored by the USP-compliant dissolution testing machine * here * the simulated fluid (Ex 1.2) or intestinal fluid (pH 7.2) must be maintained at 37 degrees. The USP 1 lysis method was used at a spin speed of 2,50 rpm. When it is tested in the proposed fluid (Ex 1.2) • During the entire test period (6.5 hours), the propellant is prevented from being released from the device. / However, when it was transferred to the pseudo-intestinal fluid (Ex. 7.2), erbium was released with a pulsatile release of 1 $ fluoropyridine after 4.5 hours K. Bao Example 10 Immediate release and pulsatile release tablets The core weight percentage of lozenges% Sumatritan (as succinate) 50 -28-A4 (210X 297 public issue) (Please read "Precautions on the back" (Fill in this page again) • Packing. • Ordering.. Lines. 5. Description of the invention (microcrystalline cellulose lactose polyvinylpyrrolidine steel stearate nafumarate β-isopropylase A6 B6 23 23 2 2 qs " In the final product, there is no Suyu Tritan K microcrystalline cellulose and lactose to dry mix. This mixture is granulated with a granular fluid made of polyvinylpyrrolidone, which is soluble in polyvinylpyrrolidone. For isopropyl fermentation, the granules are dried in a fluid bed dryer, screened with K, and mixed with sodium fumarate stearate before being compressed by a suitable tablet press in order to produce a speed of 50 mg. The 100 mg core lozenges of Matridan (as succinate) have a diameter of 5.5 mm and a thickness of 3.0 mm. Intermediate polymer layer 〃hydroxypropyl methylcellulose microcrystalline Calcium divalent calcium phosphate colloidal silica hard Acid sodium fumarate weight% 35 40 23 1 1 = * Normal viscosity in water 2 96 = 100 »Po-29-(Please first read the notes on the back and then write this page). Install. A4 (210X 297 g; ¥) A6 B6 V. Description of invention () {Please first read the notes on the back and then fill out this 11) The excipients used in the middle layer should be mixed with dry roots * and the core lozenges should be synthesized The mixture is compression coated to make 230 mg of lozenges * with a diameter of 8.7 mm and a thickness of 4.0 mm. The outer layer of Sumatratan and the core agent have the same K-square. This compression-coated lozenge further utilizes a 100 gram core mix of tablets on the compression package. Drug release is monitored using dissolution equipment that complies with USP regulations, where 900 ml of simulated fluid must be maintained at 37 t: * and used as a dissolution medium. This USP 1 dissociation method should be used at a speed of 250 revolutions per minute. Hit 0. The initial immediate release of Sumatratan was obtained. After approximately 1.5 hours Μ • The pulsating release of the ferment was followed. • Green · The core lozenges described above are also coated with the aforementioned intermediate polymer mixture · Κ is made into a lozenge with a diameter of 11.0 ft. This lozenge is further coated with an external super-speed mattelan layer mixture (100 mg ). This synthetic lozenge (7-20 gram) allows Sumatratan to be released immediately after the initial release. After 3 hours, it is the pulsatile release of the drug. Example 11 Pulsatile release lozenges -30-A4 (210X 297 public) A6 B6 V. Description of the invention () Lozenge core weight percentage% Sumatrilide (as succinic acid) 50 Microcrystalline cellulose 23 Lactose 23 Polyvinylpyrrolidone 2 Nafumarate stearate 2 * Polypropylenase qs (please read the notes on the back before writing this page). Packed. * Not shown in the final product. Hit · Sumatra Danwei microcrystalline crystalline grade vitamins and lactose lactate are mixed, and this mixture is granulated using a granular flow made of polyvinylpyrrolidone dissolved in isopropanol. The granules are dried and screened in a first-class track-bed dryer and added with Μ, and they are mixed with κ-Na-fumaric acid stearate before being compressed by an appropriate tablet-making machine to produce 50 mg of Sumatra. Dan (as succinate) 100 mcg core lozenges * It has a diameter of 5.5 mm and a thickness of 3.0 mm. Weight percentage of polymer layer% «Hydroxypropyl methylcellulose 35 Microcrystalline cellulose 40 Divalent calcium phosphate 23 Colloidal silica 1 -31-A 4 (210X 297 g; * #) A6 B6 V. Invention Description () Nafumarate stearate 1 = * 2% normal viscosity in water = 100 centipoise. The polymer excipient should be dry mixed, and the core lozenge should be made with a synthetic mixture as a compression coating to make 340 Milligrams of tablets • The diameter is 9.0 K and the thickness is 4.1 mm. The release of cascades must be monitored using dissolution equipment that complies with USP regulations, where distilled water, simulated intestinal fluid, or simulated fluid must be kept at 37 ° C and used as a dissolution medium. The USP 1 hatching method should be used at 250 rpm. After approximately 2.5 hours of each lysing medium, pulsatile release of Sumatralide can be achieved. The core lozenges described above are also coated with the aforementioned polymer mixture to produce 460 mg of lozenges with a diameter of 11 mm and a thickness of 4.5 mm. After approximately 3.5 hours of each of the aforementioned media, pulsatile release of tamatridan was achieved. Example 12 Pulsatile release lozenge core weight percentage% Zinidine pyridine hydrochloride 95 Polyvinylpyrrolidone 4 -32-A 4 (21〇X 297 male; 1ί) (Please read "Precautions on the back side before writing this book" Page) .¾. _Order · • line ·

V. Description of the invention ()

Magnesium stearate 1 Isopropanol QS w does not appear in the final product. Ranilidine hydrochloride is granulated using a bark flow of polyvinylpyrrolidone dissolved in isopropanol. The seed granules are dried in a flow bed dry biting agent, screened, and mixed with magnesium stearate before being compressed in an appropriate tablet® machine to produce a 150-crane pyridine (as a Base) of 177 mcg core tablets, its diameter is 7.5 mm • and the thickness is 4.5 mm. (Please read the precautions on the back before filling out this page) • Outfit · Percentage of outer layer weight% = * Hydroxypropyl methylcellulose 23.0 Microcrystalline Vedicolin 40.6 Divalent calcium phosphate 35.0 Colloidal silica 0.7 Nafumarate stearate 0.7 • dozen. • green. • Normal viscosity of 2 96 in water = 100 centipoise. The excipients in the outer layer are mixed with dry gourd, and the core lozenges are made with a synthetic mixture as a compression coating. 7 30 mcg lozenges • Its diameter is 12 mm, and its thickness is 5.6 cm eaves. -33-% by weight 95 A6 _B6 V. Description of the invention () The release of the drug should be monitored using a dissolution device that complies with USP regulations. • Here, 900 ml of simulated gastric fluid is kept at 37 t: and used as a dissolution medium . The USP 1 dissolving method is used at a speed of 250 revolutions per minute, and the pulsatile release of the chaff is obtained after about 3 hours. Example 13 Immediate release and pulsatile release lozenges A pulsatile delivery device containing ranidine was made as described in Example 1. This compressed coated lozenge was further compressed using a suitable tablet press to coat 177 Mg of lozenge core mixture. The release of cascades is monitored using dissolution equipment that complies with USP regulations. * Here, the simulated gastric flow condyle of 900 ml is maintained at 371: and used as a dissolution medium. Used at a speed of 250 revolutions per minute (JSP 1 dissolution method. The initial immediate release of ranidine was obtained • After 3 hours, followed by the pulsatile release of the drug. Example 14 Pulse release of lozenge H agent core ranidine pyridine hydrochloride Polyvinylpyrrolidone-3 4-f 4 (21〇X 297 异 发) (please read "Precautions on the back side and then fill out this page") • Pack · • fight · 5. Description of the invention (A6 B6 Magnesium stearate 0.5 * Isopropanol qs-Ranilidine hydrochloride does not appear in the final product. It is granulated using a granular fluid made of polyvinylpyrrolidone dissolved in isopropanol. This granule is dried in the fluid bed The smelter is dried, sieved, and mixed with magnesium stearate prior to shrinkage in a conventional tablet press to make 177-gram core lozenges containing 150 grams of dinipyridine (as a base) , The diameter is 9.0 mm and the thickness is 3.4 mm. The outer layer «hydroxypropyl methylcellulose microcrystalline form of divalent calcium phosphate divalent calcium phosphate colloidal silicon dioxide sodium fumarate stearate% 35.0 40.0 23.0 (please read "Notes on the back before filling this page") • Beat-.green. Normal viscosity of β in water 2% = 100 centipoise. Excipients must be mixed with dry stem * and the core tablets should be coated with synthetic mixture to make 530 mg. Lozenges with a diameter of 12 mm and a thickness of 5.1 mm. -35 A4 (210X 297 public) A6 _B6 5. Description of the invention () f Please read the precautions on the back before filling this page) Medicine The release should be monitored using the USP-compliant lysis kit. • Here, the 900 mL of the sacral stream should be maintained at 371 and used as the dissolution medium. The USP 1 dissolution method is used at a speed of 2 50 rpm. The pulsatile release of the drug is obtained after about 2 hours M. Example 15 Pulsatile release lozenges Lozenge core weight% Ranylpyridinium hydrochloride 95 Polyvinylpyrrolidone 4.5 Magnesium stearate 0.5 * Isozyme qs-dozen * Does not appear in the final product. &Quot; Raney pyridine hydrochloride is granulated using a granular fluid made of polyvinylpyrrolidone dissociated in isopropanol. Such granules are dried in a fluid bed dryer Dry 堍 * to be screened and compressed in a common tablet Before compression, it was mixed with magnesium stearate to make a 177 mg core tablet containing 150 μg of difenidyl (as a base), with a diameter of 7.5 mm and a thickness of 4.5 mm. The outer layer weight percentage%- 36-A 4 (210X 297'a '; *!) ^^ 9236 V. Description of the invention () Hydroxypropyl methyl kinoxin 33.3 Microcrystalline cellulose 38.1 Divalent calcium phosphate 26.7 Colloidal silica 0.95 Hard Nafumarate fatty acid 0.95-2% normal viscosity in water = 100 centipoise. The excipients in the outer layer are dry mixed * and the core lozenges are compressed and coated with a synthetic mixture to make 530-gram tablets. Its diameter is 12 mm and its thickness is 5.1 cm. The release of cascades is monitored using dissolution equipment that complies with USP regulations. * Here, 900 ml of simulated gastric fluid is maintained at 311C and is used as a dissolution medium. The USP 1 dissolution method was used at a speed of 250 revolutions per minute. After about 3 hours, the pulsatile release of the drug was obtained. (Please pay attention to the matters on the back of the moraine first, and then fill out this page) • Install · · Play · · Green. A 4 (210X 2971 'hair)

Claims (1)

No. 8U〇8R15 Patent Application Case Α8 Β8 Youyou 藞 patent scope and then repair ΕΕ 太 (85 years 1 use ^ D8 public warehouse, apply for patent scope repair ι supplement a kind of 荹 荜 姐 Compound, including: iai -Outer two, which contains 2 3-77¾ w / w of hydroxypropyl methyl kinetin and microcrystalline cellulose selected from "-" ^ especially ^ or ^: ^: ^ contained calcium hydrogen phosphate or The filler of the mixture; and the layer quickly.,... 0, the external PH2 type in addition to a U of the salt co-transfer layer has Μ in the element gradually with Η which is connected to clear the Η, blood can be removed; and In addition, W medicine, part erosion, and medicine M are combined into medicines, and the resistance of ¾ group and the disintegration of the layer or the active strength of the disintegrating drug e) • The dissolution rate of S 1 1 η Η 2 species Xu Xun. The circling item id is from the back to the inner ring item 3542lt. The optional dance fan 1 clothing lssaη has the first package of the Chinese medicine (Γ containing the agent 30: 5. Layer 1 ligalilin element external exposure 1: The special supplement Lei Neiqing should lie in the request. Please refer to the application of a solution in the blood. The layer ratio is based on the root speed of the root (M). (Please read the precautions on the back before writing the clothing page) 4. According to item 1 or 2 of the patent scope of the application, the sister compound * where the serotonin synergist is Runatriptan or its Pharmaceutically acceptable salts, and the serotonin orange resistance agent is 5-fluoro-2-methoxy-1H-indole-3-carboxylic acid [1- [2-[(methylsulfonyl) amino] Ethyl] -4-hexahexapyridinyl] methyl ester; ondansetron; 2,3,4,5-tetrahydro-5-methyl-2-Π5-methyl-Id-quinazole -4-yl) methyl] -1L-pyridine [4,3bl indole-1-one; (+)-1,2,3,9-tetrahydro-9-shenyl_3-[< 5 -Methyl-1H_-squinted-4-yl) methyl] -4 H_-carbazol-4-one; 6-fluoro-2,3,4.5-tetracolumn-5-methylpyridine-2-[(5 -Methyl-1L-imidazol-4-yl) methyl] -ld_-pyridine [4, 3-b] indole-copper copper; or its pharmaceutically acceptable Elder K dissolves the compound. The size of the clothing paper is applicable to the national standard of China (CNS) A4 Diange UUI X m public wear) A8 B8 C8 D8 6. Application for patent scope 5. The pharmaceutical composition according to item 1 of the scope of patent application, in which the hydroxyl group The normal viscosity of propyl methyl semenol in water at 2% is 100 mols. 6. The pharmaceutical composition of No. 1 in the application scope of Genzao, in which the outer layer additionally contains a lubricant and a slip agent. 7. A method of preparing a pharmaceutical composition according to item 1 of the patent application scope, which contains hydroxypropyl methylcellulose and an outer layer of a filler selected from " Self-Crystalline Vitamin D and calcium hydrogen phosphate or a mixture thereof. The substance is compressed and coated on an inner core containing active ingredients. 8. Root Neem's Patent Application Method No. 7 ", in which the S-medicine compound is further shrink-coated with an active ingredient-containing blend. This paper standard is applicable to the National Singing Apple (CNS) 8 4 gauge branding (2 ΙΟ X 21) 7 Gongsheng) ------- ^ Packing --------- order ---- -丄-线 (Please read the notes on the back before writing this page)